Tricyclic inhibitors of matrix metalloproteinases

ABSTRACT

Tricyclic compounds are described as well as methods for the preparation and pharmaceutical compositions of same, which are useful as inhibitors of matrix metalloproteinases, particularly gelatinase A (72 kD gelatinase) and stromelysin-1 and for the treatment of multiple sclerosis, atherosclerotic plaque rupture, aortic aneurism, heart failure, restenosis, periodontal disease, corneal ulceration, cancer metastasis, tumor angionenesis, arthritis, or other autoimmune or inflammatory disorders dependent upon tissue invasion by leukocytes.

BACKGROUND OF THE INVENTION

The present invention relates to novel tricyclic compounds useful aspharmaceutical agents, to methods for their production, topharmaceutical compositions which include these compounds and apharmaceutically acceptable carrier, and to pharmaceutical methods oftreatment. The novel compounds of the present invention are inhibitorsof matrix metalloproteinases, e.g., gelatinase A (72 kDa gelatinase) andstromelysin-1. More particularly, the novel compounds of the presentinvention are useful in the treatment of atherosclerotic plaque rupture,aortic aneurism, heart failure, restenosis, periodontal disease, cornealulceration, cancer metastasis, tumor angiogenesis, arthritis, multiplesclerosis, and other autoimmune or inflammatory disorders dependent onthe tissue invasion of leukocytes or other activated migrating cells.

Gelatinase A and stromelysin-1 are members of the matrixmetalloproteinase (MMP) family (Woessner J. F., FASEB J.1991;5:2145-2154). Other members include fibroblast collagenase,neutrophil collagenase, gelatinase B (92 kDa gelatinase), stromelysin-2,stromelysin-3, matrilysin, collagenase. 3 (Freije J. M., Diez-Itza I.,Balbin M., Sanchez L. M., Blasco R., Tolivia J., and Lopez-Otin C. J.Biol. Chem., 1994;269:16766-16773), and the newly discoveredmembrane-associated matrix metalloproteinases (Sato H., Takino T., OkadaY., Cao J., Shinagawa A., Yamamoto E., and Seiki M., Nature,1994;370:61-65).

Matrix metalloproteinases share high sequence hemology and the catalyticdomains of each of the MMPs can be identified by sequence alignment. Thegene for the catalytic domain of stromelysin-1, SCD, was constructed byremoving the propeptide and C-terminal domain (Ye Q.-Z., Johnson L. L,Hupe D. J., and Baragi V., "Purification and Characterization of theHuman Stromelysin Catalytic Domain Expressed in Escherichia coli",Biochemistry, 1992;31:11231-11235). The gelatinase A catalytic domain,GCD, was similarly constructed with the additional removal of thefibronectin-like insert which interrupts the catalytic domain (Ye Q.-Z.,Johnson L. L., Yu A. E., and Hupe D., "Reconstructed 19 kDa CatalyticDomain of Gelatinase A is an Active Proteinase", Biochemistry,1995;34:4702-4708). Both truncated proteins cleave synthetic peptidesubstrates and the natural substrates proteoglycan and gelatin in amanner similar to the full-length enzymes and can be used to identifymatrix metalloproteinase inhibitors.

The catalytic zinc in matrix metalloproteinases is the focal point forinhibitor design. The modification of substrates by introducingchelating groups has generated potent inhibitors such as peptidehydroxymates, thio-containing peptides, and N-carboxyalkyl peptides.Peptide hydroxymates and the natural endogenous inhibitors of MMPs(TIMPs) have been used successfully to treat animal models of cancer andinflammation. However, except for amino acid derivatives with weakpotency (Ye Q.-Z., Johnson L. L., Nordan I., Hupe D., and Hupe L., J.Med. Chem. 1994;37(1):206-209), few non-peptide inhibitors have beendescribed or shown to have in vivo activity.

The ability of the matrix metalloproteinases to degrade variouscomponents of connective tissue makes them potential targets forcontrolling pathological processes. For example, the rupture ofatherosclerotic plaques is the most common event initiating coronarythrombosis. Destabilization and degradation of the extracellular matrixsurrounding these plaques by MMPs has been proposed as a cause of plaquefissuring. The shoulders and regions of foam cell accumulation in humanatherosclerotic plaques show locally increased expression of gelatinaseB, stromelysin-1, and interstitial collagenase. In situ zymography ofthis tissue revealed increased gelatinolytic and caseinolytic activity(Galla Z. S., Sukhova G. K., Lark M. W., and Libby P., "Increasedexpression of matrix metalloproteinases and matrix degrading activity invulnerable regions of human atherosclerotic plaques", J. Clin. Invest.,1994;94:2494-2503). In addition, high levels of stromelysin RNA messagehave been found to be localized to individual cells in atheroscleroticplaques removed from heart transplant patients at the time of surgery(Henney A. M., Wakeley P. R., Davies M. J., Foster K., Hembry R., MurphyG., and Humphries S., "Localization of stromelysin gene expression inatherosclerotic plaques by in situ hybridization", Proc. Nat'l. Acad.Sci. 1991;88:8154-8158).

Inhibitors of matrix metalloproteinases will have utility in treatingdegenerative aortic disease associated with thinning of the medialaortic wall. Increased levels of the proteoiytic activities of MMPs havebeen identified in patients with aortic aneurisms and aortic stenosis(Vine N. and Powell J. T., "Metalloproteinases in degenerative aorticdiseases", Clin. Sci., 1991;81:233-239).

Heart failure arises from a variety of diverse etiologies, but a commoncharacteristic is cardiac dilation which has been identified as anindependent risk factor for mortality (Lee T. H., Hamilton M. A.,Stevenson L. W., Moriguchi J. D., Fonarow G. C., Child J. S., Laks H.,and Walden J. A., "Impact of left ventricular size on the survival inadvanced heart failure", Am. J. Cardiol., 1993;72:672-676). Thisremodeling of the failing heart appears to involve the breakdown ofextracellular matrix. Matrix metalloproteinases are increased inpatients with both idiopathic and ischemic heart failure (Reddy H. K.,Tyagi S. C., Tjaha I. E., Voelker D. J., Campbell S. E., Weber K. T.,"Activated myocardial collagenase in idiopathic dilated cardiomyopathy",Clin. Res., 1993;41:660A; Tyagi S. C., Reddy H. K., Voelker D., Tjara I.E., Weber K. T., "Myocardial collagenase in failing human heart", Clin.Res., 1993;41:681A). Animal models of heart failure have shown that theinduction of gelatinase is important in cardiac dilation (Armstrong P.W., Moe G. W., Howard R. J., Grima E. A., Cruz T. F., "Structuralremodeling in heart failure: gelatinase induction", Can. J. Cardiol.,994;10:214-220), and cardiac dilation precedes profound deficits incardiac function (Sabbah H. N., Kono T., Stein P. D., Mancini G. B.,Goldstein S., "Left ventricular shape changes during the course ofevolving heart failure", Am. J. Physiol., 1992;263:H266-H270).

Neointimal proliferation, leading to restenosis, frequently developsafter coronary angioplasty. The migration of vascular smooth musclecells (VSMCs) from the tunica media to the neointima is a key event inthe development and progression of many vascular diseases and a highlypredictable consequence of mechanical injury to the blood vessel(Bendeck M. P., Zempo N., Clowes A. W., Galardy R. E., Reidy M., "Smoothmuscle cell migration and matrix metalloproteinase expression afterarterial injury in the rat", Circulation Research, 1994;75:539-545).Northern blotting and zymographic analyses indicated that gelatinase Awas the principal MMP expressed and excreted by these cells. Further,antisera capable of selectively neutralizing gelatinase A activity alsoinhibited VSMC migration across basement membrane barrier. After injuryto the vessel, gelatinase A activity increased more than 20-fold asVSCMs underwent the transition from a quiescent state to aproliferating, motile phenotype (Pauly R. R., Passaniti A., Bilato C.,Monticone R., Cheng L., Papadopoulos N., Gluzband Y. A., Smith L.,Weinstein C., Lakatta E., Crow M. T., "Migration of cultured vascularsmooth muscle cells through a basement membrane barrier requires type IVcollagenase activity and is inhibited by cellular differentiation",Circulation Research, 1994;175:41-54).

Collagenase and stromelysin activities have been demonstrated infibroblasts isolated from inflamed gingiva (Uitto V. J., Applegren R.,Robinson P. J., "Collagenase and neutral metalloproteinase activity inextracts from inflamed human gingiva", J. Periodontal Res.,1981;16:417-424), and enzyme levels have been correlated to the severityof gum disease (Overall C. M., Wiebkin O. W., Thonard J. C.,"Demonstrations of tissue collagenase activity in vivo and itsrelationship to inflammation severity in human gingiva", J. PeriodontalRes., 1987;22:81-88). Proteolytic degradation of extracellular matrixhas been observed in corneal ulceration following alkali burns (Brown S.I., Weller C. A., Wasserman H. E., "Collagenolytic activity of alkaliburned corneas", Arch. Opthalmol., 1969;81:370-373). Thio-containingpeptides inhibit the collagenase isolated from alkali-burned rabbitcorneas (Burns F. R., Stack M. S., Gray R. D., Paterson C. A., Invest.Opththamol., 1989;30:1569-1575).

Davies, et al. (Cancer Res., 1993;53:2087-2091) reported that a peptidehydroxymate, BB-94, decreased the tumor burden and prolonged thesurvival of mice bearing human ovarian carcinoma xenografts. A peptideof the conserved MMP propeptide sequence was a weak inhibitor ofgelatinase A and inhibited human tumor cell invasion through a layer ofreconstituted basement membrane (Melchiori A., Albili A., Ray J. M., andStetler-Stevenson W. G., Cancer Res., 1992;52:2353-2356), and thenatural tissue inhibitor of metalloproteinase-2 (TIMP-2) also showedblockage of tumor cell invasion in in vitro models (DeClerck Y. A.,Perez N., Shimada H., Boone T. C., Langley K. E., and Taylor S. M.,Cancer Res., 1992;52:701-708). Studies of human cancers have shown thatgelatinase A is activated on the invasive tumor cell surface (A. Y.Strongin, B. L. Marmer, G. A. Grant, and G. I. Goldberg, J. Biol Chem.,1993;268:14033-14039) and is retained there through interaction with areceptor-like molecule (Monsky W. L., Kelly T., Lin C.-Y., Yeh Y.,Stetler-Stevenson W. G., Mueller S. C., and Chen W.-T., Cancer Res.,1993;53:3159-3164).

Inhibitors of MMPs have shown activity in models of tumor angiogenesis(Taraboletti G., Garofalo A., Belotti D., Drudis T., Borsotti P.,Scanziani E., Brown P. D., and Giavazzi R., Journal of the NationalCancer Institute, 1995;87:293 and Benelli R., Adatia R., Ensoli B.,Stetler-Stevenson W. G., Santi L., and Albini A., Oncology Research,1994;6:251-257).

Several investigators have demonstrated consistent elevation ofstromelysin and collagenase in synovial fluids from rheumatoid andosteoarthritis patients as compared to controls (Walakovits L. A., MooreV. L., Bhardwaj N., Gallick G. S., and Lark M. W., "Detection ofstromelysin and collagenase in synovial fluid from patients withrheumatoid arthritis and posttraumatic knee injury", Arthritis Rheum.,1992;35:35-42; Zafarullah M., Pelletier J. P., Cloutier J. M., andMarcel-Pelletier J., "Elevated metalloproteinases and tissue inhibitorof metalloproteinase mRNA in human osteoarthritic synovia", J.Rheumatol., 1993;20:693-697). TIMP-1 and TIMP-2 prevented the formationof collagen fragments, but not proteoglycan fragments, from thedegradation of both the bovine nasal and pig articular cartilage modelsfor arthritis, while a synthetic peptide hydroxymate could prevent theformation of both fragments (Andrews H. J., Plumpton T. A., Harper G.P., and Cawston T. E., Agents Actions, 1992;37:147-154; Ellis A. J.,Curry V. A., Powell E. K., and Cawston T. E., Biochem. Biophys. Res.Commun., 1994;201:94-101).

Gijbels, et al., (J. Clin. Invest. 1994;94:2177-2182) recently describeda peptide hydroxymate, GM6001, that suppressed the development orreversed the clinical expression of experimental allergicencephalomyelitis (EAE) in a dose dependent manner, suggesting the useof MMP inhibitors in the treatment of autoimmune inflammatory disorderssuch as multiple sclerosis.

Multiple sclerosis (MS) is a complex demyelinating disease of thecentral nervous system (CNS) characterized by inflammation, disruptionof the blood-brain barrier, selective destruction of the myelin sheathswith glial scar formation and loss of neuronal cell conductivity leadingto neurological deficits. The underlying cause is unknown, but it hasbeen established as a T-cell mediated autoimmune disease (LawrenceSteinman, "Autoimmune Disease", Scientific American, September1993;269(3):106-114). While there are no spontaneous animal models forthe disease, experimental allergic encephalomyelitis (EAE) has been usedsuccessfully to study many aspects of MS pathogenesis, and the work ofPaterson and others has clearly and convincingly demonstrated thevalidity of this model as the only accepted preclinical test forefficacy of agents in MS (Paterson P., "Going to the Rats and Dogs toStudy the Patient," Cell-Immunol., 1983;82(1):55-74). Bornstein's workusing mammalian organotypic cultures showed that the CNS tissueresponded with identical patterns of demyelination, swollen myelinsheaths, and eventual "sclerosis" when exposed to serum fromEAE-affected animals and MS patients (Bornstein M. B., Miller A. I.,Slagle S., Arnon R., Sela M., and Teitelbaum D., "Clinical Trials ofCopolymer I in Multiple Sclerosis," in Annals of the New York Academy ofSciences, eds Labe Scheinberg and Cedric S. Raine, 1984;36:366-372).Analysis of the receptors on T-cells isolated from brain lesions of MSpatients reveal that they are reactive to a peptide fragment of myelinbasic protein analogous to the antigen used to precipitate the EAE model(Lawrence Steinman and Paul Conlon, "Designing rational therapies formultiple sclerosis," Bio/technology, February 1995:118-120).

Several successful therapeutic strategies for treating MS target theT-cell response modeled in EAE. Beta-interferon (betaseron), acts inpartby downregulating the expression of histocompatibility locus antigen(HLA) DR2. EAE studies have been used as the primary experimental basisto develop many of the current treatments for MS. Copolymer-1 and oraladministration of myetin basic protein act by inducing immune toleranceto the myelin basic protein (MBP) antigen. The EAE model was used todevelop a therapy in which peptides derived from the T-cell receptor Vregion recognizing an MBP fragment are used to immunize patients withrelapsing-remitting MS. Monoclonal antibodies (Mab) against the CD4receptor prevented the clinical and histological manifestations of EAE(Steinman L., Lindsey J. W., Alters S., and Hodgkinson S., "Fromtreatment of experimental allergic encephalomyetitis to clinical trialsin multiple sclerosis," Immunol-Ser., 1993;59:253-60). Clinical trialsof CD4 Mabs are being conducted by several companies.

In MS and EAE, the blood-brain barrier has been shown to be defectiveboth with respect to exclusion of blood-borne substances from the CNSand infiltration of lymphocytes (Lam D. K. C., "The central nervoussystem barrier in acute experimental allergic encephalomyelitis," in TheBlood Brain Barrier in Health and Disease, edited by Suckling A. J.,Rumsby M. G., and Bradbury M. W. B., 1986:158-164, Ellis Horwood, Ltd.,Chichester, UK). Using gadolinium-DTPA enhanced magnetic resonanceimaging (MRI), Miller, et al. (Miller D. H., Rudge P., Johnson G.,Kendall B. E., MacManus D. G., Moseley I. F., Barnes D., and McDonald W.I., "Serial gadolinium enhanced magnetic resonance imaging in multiplesclerosis, " Brain, 1988;111:927-939) showed in a serial study of MSpatients that in recognizable new lesions or in new parts of existinglesions, blood-brain barrier impairment was always present. It appearsthat blood-brain barrier disruption is the beginning of an irreversiblecascade of events leading to demyelination (Barkhof F., Hommes O. R.,Scheltens P., and Valk J., "Quantitative MRI changes in gadolinium-DPTAenhancement after high-dose intravenous methyl-prednisolone in multiplesclerosis, " Neurology, 1991;14:1219-1222) and is necessary for thedevelopment of the disease (Moor A. C. E., De Vries H. E., De Boer A.G., and Breimer D. D., Biochemical Pharmacology, 1994;47:1717-1724).Previously, it has been shown that neutralizing antibodies to celladhesion molecules prevent lymphocyte infiltration in the EAE, and thatthis inhibits the inflammatory response initiating the encephalomyelitis(Yednock T. A., Cannon C., Fritz L. C., Sanchez-Madrid F., Steinman L.,and Karin N., "Prevention of experimental autoimmune encephalomyelitisby antibodies against α4 β1 integrin," Nature, Mar. 5,1992;356(6364):63-66). It has therefore been predicted that agents thatprevent such infiltration may be among the most inviting prospects fortherapy in MS.

The mechanism through which the blood-brain barrier is disrupted duringthe pathogenesis of MS and other inflammatory diseases of the centralnervous system is under intense study. Rosenberg, et al. showed thatactivated gelatinase A injected intracerebrally attacks extracellularmatrix and opens the blood-brain barrier. Treatment with TIMP-2 reducedthe proteolysis and protected the blood-brain barrier. (Rosenberg G. A.,Kornfeld M., Estrada E., Kelley R. O., Liotta L., and Stetler-StevensonW. G., "TIMP-2 reduces proteolytic opening of the blood-brain barrier bytype IV collagenase", Brain Research, 1992;576:203-207). A recent studyby Madri has elucidated the role of gelatinase A in the extravasation ofT-cells from the blood stream during inflammation (Ramanic A. M., andMadri J. A., "The Induction of 72-kD Gelatinase in T Cells upon Adhesionto Endothelial Cells is VCAM-1 Dependent", J. Cell Biology,1994;125:1165-1178). This transmigration past the endothelial cell layeris coordinated with the induction of gelatinase A and is mediated bybinding to the vascular cell adhesion molecule-1 (VCAM-1). Once thebarrier is compromised, edema and inflammation are produced in the CNS.Leukocytic migration across the blood-brain barrier is known to beassociated with the inflammatory response in EAE. Inhibition of themetalloproteinase gelatinase A would block the degradation ofextracellular matrix by activated T-cells that is necessary for CNSpenetration.

These studies provide the basis for the expectation that an effective,bioavailable inhibitor of gelatinase A and/or stromelysin-1 would havevalue in the treatment of diseases involving disruption of extracellularmatrix resulting in inflammation due to lymphocytic infiltration,inappropriate migration of metastatic or activated cells, or loss ofstructural integrity necessary for organ function.

We have identified a series of tricyclic compounds that are inhibitorsof matrix metalloproteinases, particularly gelatinase A andstromelysin-1, and are additionally active in an allergicencephalomyelitis model and thus useful as agents for the treatment ofmultiple sclerosis, atherosclerotic plaque rupture, restenosis, aorticaneurism, heart failure, periodontal disease, corneal ulceration, cancermetastasis, tumor angiogenesis, arthritis, or other autoimmune orinflammatory diseases dependent upon tissue invasion by leukocytes.

SUMMARY OF THE INVENTION

Accordingly, the present invention is a compound of Formula I ##STR1##wherein one of R¹ or R² is ##STR2## wherein X is O,

N--OR⁶ wherein R⁶ is hydrogen,

--(CH₂)_(n) -aryl wherein n is zero or an integer of 1 to 5,

alkyl, or

--(CH₂)_(n) -cycloalkyl wherein n is as defined above, or ##STR3##wherein R⁶ and R^(6a) are each the same or different and each is asdefined above for R⁶ ;

R and R^(a) are each the same or different and each is

hydrogen,

--(CH₂)_(n) -aryl wherein n is as defined above,

--(CH₂)_(n) -heteroaryl wherein n is as defined above,

--(CH₂)_(p) --R⁷ --(CH₂)_(q) -aryl wherein R⁷ is O or S and p or q iseach zero or an integer of 1 to 5 and the sum of p+q is not greater thanan integer of 5,

--(CH₂)_(p) --R⁷ --(CH₂)_(q) -heteroaryl wherein p, q, and R⁷ are asdefined above,

alkyl,

--(CH₂)_(n) -cycloalkyl wherein n is as defined above, or

--(CH₂)_(r) --NH₂ wherein r is an integer of 1 to 9;

a is zero or an integer of 1 to 3;

R⁵ is

OH,

OR⁶ wherein R⁶ is as defined above, ##STR4## wherein R⁶ and R^(6a) areeach the same or different and are as defined above for R⁶, or

NH--OR⁶ wherein R⁶ is as defined above;

R³ and R⁴ are each the same or different and each is

hydrogen,

alkyl,

NO₂,

halogen,

OR⁶ wherein R⁶ is as defined above,

CN,

CO₂ R⁶ wherein R⁶ is as defined above,

SO₃ R⁶ wherein R⁶ is as defined above,

CHO, ##STR5## wherein R is as defined above, ##STR6## wherein R⁶ andR^(6a) are each the same or different and are as defined above for R⁶,or ##STR7## wherein R⁶ and R^(6a) are each the same or different and areas defined above for, R⁶ ;

W, W¹, Z, and Z¹ are each the same or different and each is CR³ whereinR³ is as defined above, or N providing only one of W or W¹ is N and/oronly one of Z or Z¹ is N; and

Y is ##STR8## wherein R is as defined above, --O--,

--S--(O)_(m) -- wherein m is zero or an integer of 1 or 2,

--CH₂ --, ##STR9## wherein R⁶ is as defined above, ##STR10## wherein R⁶is as defined above, ##STR11## wherein R⁶ and R^(6a) are the same ordifferent and are as defined above for R⁶, ##STR12## wherein R⁶ is asdefined above, ##STR13## WHEREIN R⁶ is as defined above, ##STR14## --CH₂--O--, --O--CH₂ --,

--CH₂ --S(O)_(m) -- wherein m is as defined above,

--S(O)_(m) --CH₂ -- wherein m is as defined above, ##STR15## wherein R⁶is as defined above, ##STR16## wherein R⁶ is as defined above, --CH═N--,or

--N═CH--;

with the proviso that when X is O, and R⁵ is not NH--OR⁶, at least oneof R or R^(a) is not hydrogen; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

As matrix metalloproteinase inhibitors, the compounds of Formula I areuseful as agents for the treatment of MS. They are also useful as agentsfor the treatment of atherosclerotic plaque rupture, restenosis,periodontal disease, corneal ulceration, cancer metastasis, tumorangiogenesis, arthritis, and other inflammatory disorders dependent upontissue invasion by leukocytes.

A still further embodiment of the present invention is a pharmaceuticalcomposition for administering an effective amount of a compound ofFormula I in unit dosage form in the treatment methods mentioned above.Finally, the present invention is directed to methods for production ofcompounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from 1 to 8 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,and the like.

"Alkoxy" and "thioalkoxy" are O-alkyl or S-alkyl of from 1 to 6 carbonatoms as defined above for "alkyl".

The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8carbon atoms and includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group, aphenyl group substituted by 1 to 4 substituents selected from alkyl asdefined above, alkoxy as defined above, thioalkoxy as defined above,hydroxy, halogen, trifluoromethyl, amino, alkylamino as defined abovefor alkyl, dialkylamino as defined for alkyl, nitro, cyano, carboxy, SO₃H, CHO, ##STR17## as defined above for alkyl, ##STR18## as defined abovefor alkyl, ##STR19## as defined above for alkyl, --(CH₂)_(n) 2--NH₂wherein n² is an integer of 1 to 5, --(CH₂)_(n) 2--NH-alkyl as definedabove for alkyl and n², --(CH₂)_(n) 2--N(alkyl)₂ as defined above foralkyl and n².

The term "heteroaryl" means a heteroaromatic radical and includes, forexample, which is 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl,2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3- or4-pyridazinyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl.

"Halogen" is fluorine, chlorine, bromine, or iodine.

Phenyl is abbreviated "Ph".

Some of the compounds Of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono- and dicarboxylicacids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids,alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonicacids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate,oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate,mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate,lactate, maleate, tartrate, methanesulfonate, and the like. Alsocontemplated are salts of amino acids such as arginate and the like andgluconate, galacturonate (see, for example, Berge S. M., et al,"Pharmaceutical Salts," J. of Pharma Sci., 1977;66:1.

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. The free base formmay be regenerated by contacting the salt form with a base and isolatingthe free base in the conventional manner. The free base forms differfrom their respective salt forms somewhat in certain physical propertiessuch as solubility in polar solvents, but otherwise the salts areequivalent to their respective free base for purposes of the presentinvention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. ofPharma Sci., 1977;66:1.

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. The free acid formmay be regenerated by contacting the salt form with an acid andisolating the free acid in the conventional manner. The free acid formsdiffer from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid for purposes of the presentinvention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all diastereomeric,enantiomeric, and epimeric forms as well as the appropriate mixturesthereof. Additionally, the compounds of the present invention may existas geometric isomers. The present invention includes all cis, trans,syn, anti, entgegen (E), and zusammen (Z) isomers as well as theappropriate mixtures thereof.

In one embodiment of the invention, a preferred compound of Formula I isone wherein

W, W¹, Z, and Z¹ are CR³ ; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein

Y is ##STR20## --O--, --S--(O)_(m) --,

--CH₂ --, ##STR21## and corresponding isomers thereof; orpharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein one of R or R^(a) is other than hydrogen; and correspondingisomers thereof; or a pharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein X is N--OR⁶ ; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein R⁵ is OH; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein Y is --O--; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein X is N--OH; Y is --O--; and R³ and R⁴ are each hydrogen; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

Another preferred compound of Formula I of this embodiment is onewherein X is O and R⁵ is NH--OR⁶ ; and corresponding isomers thereof; ora pharmaceutically acceptable salt thereof.

In another embodiment of the invention, a preferred compound of FormulaI is one wherein W, W¹, Z, and Z¹ is N providing only one of W or W¹ isN and/or only one of Z or Z¹ is N; and corresponding isomers thereof; ora pharmaceutically acceptable salt, thereof.

Another preferred compound of Formula I of this embodiment is onewherein

Y is ##STR22## --O--, --S--(O)_(m) --,

--CH₂ --, ##STR23## and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein one of R or R^(a) is other than hydrogen; and correspondingisomers thereof; or a pharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein X is N--OR⁶ ; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein R⁵ is OH; and corresponding isomers thereof, or apharmaceutically acceptable salt thereof.

Another preferred compound of Formula I of this embodiment is onewherein X is O and R⁵ is NH--OR⁶ ; and corresponding isomers thereof; ora pharmaceutically acceptable salt thereof.

Particularly valuable is a compound selected from the group consistingof:

4-Dibenzofuran-2-yl-4-hydroxyimino-butyric acid;

2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-4-methyl-pentanoic acid;

2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-phenyl-pentanoic acid;

4-Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid;

5-(4-Chloro-phenyl)-2-(2-dibenzofuran-2-yl-2-hydroxyimino-ethyl)-pentanoicacid;

2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-fluoro-phenyl)-pentanoicacid;

2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-methoxy-phenyl)-pentanoicacid;

2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-p-tolyl-pentanoic acid;

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-methyl-hexanoic acid;

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-phenyl-hexanoic acid;

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-phenyl-pentanoic acid;

6-(4-Chloro-phenyl)-3-(dibenzofuran-2-yl-hydroxyimino-methyl)-hexanoicacid;

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-fluoro-phenyl)-hexanoicacid;

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxyphenyl)-hexanoicacid; and

3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoic acid; and

corresponding isomers thereof; or a pharmaceutically acceptable saltthereof.

More particularly valuable is 4-dibenzofuran-2-yl-4-hydroxyimino-butyricacid; and corresponding isomers thereof; or a pharmaceuticallyacceptable salt thereof.

The compounds of Formula I are valuable inhibitors of gelatinase Aand/or stromelysin-1. It has been shown previously that inhibitors ofmatrix metalloproteinases have efficacy in models of disease states likearthritis and metastasis that depend on modification of theextracellular matrix. We demonstrate here that potent and specificinhibitors of gelatinase A also have activity in the rat experimentalallergic encephalomyelitis model which is predictive for human multiplesclerosis and has previously been used as a basis for predicting theefficacy of other therapeutic agents for MS, including anti-CD4monoclonal antibody, copolymer I, betaseron, cyclosporin, and MBP oralantigen.

In vitro experiments were carried out which demonstrate the efficacy ofcompounds of Formula I as potent and specific inhibitors of gelatinase Aand stromelysin-1, while showing lesser or no inhibition of otherrelated matrix metalloproteinases. Experiments were carried out withboth the full-length enzymes and the catalytic domains. Table I showsthe activity of Example 2 versus GCD (recombinant gelatinase A catalyticdomain); gelatinase A (recombinant full-length enzyme); SCD(stromelysin-1 catalytic domain); stromelysin-1 (full-length nativeenzyme); gelatinase B (recombinant full-length enzyme); and collagenase(full-length native enzyme). IC₅₀ values were determined using athiopeptolide substrate, Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt (YeQ.-Z., Johnson L. L., Hupe D. J., and Baragi V., "Purification andCharacterization of the Human Stromelysin Catalytic Domain Expressed inEscherichia coli", Biochemistry, 1992;31:11231-11235). Example 2inhibits the conversion of the substrate by gelatinase A with an IC₅₀value of 1.31 μM. The same compound also inhibits stromelysin-1 with anIC₅₀ value of 7.64 μM. IC₅₀ values for gelatinase B, and collagenase,were >100 μM.

                  TABLE I                                                         ______________________________________                                                      Example 2 IC.sub.50                                             Enzyme        (μM)                                                         ______________________________________                                        GCD           0.040                                                           Gelatinase A  1.31                                                            SCD           7.12                                                            Stromelysin   7.64                                                            Gelatinase B  >100                                                            Collagenase   >100                                                            ______________________________________                                    

The activity of Example 2 in suppressing the inflammatory diseaseassociated with EAE was tested using the Lewis rat acute model. FemaleLewis rats were purchased from Harlan Sprague-Dawley (Indianapolis,Ind.) and were used at 8 to 10 weeks of age. Active EAE was induced byinjection of 0.05 mL emulsion of myelin basic protein (MBP) withcomplete Freund's adjuvant (CFA), containing 25 μg guinea pig MBP and100 μg Mycobacterium butyricum (Difco Laboratories, Detroit, Mich.) intoone hind footpad. Immunized rats were observed daily for clinical signsof EAE and scored as follows: 0, no symptoms; 1, loss of tail tonicity;2, paresis; 3, hind limb paralysis, often accompanied by incontinence;and 4, death. Formalin-fixed brain slice sections were stained withhematoxylin-eosin and evaluated microscopically for perivascular andparenchymal infiltration. Compound was administered by gavage as asolution in sterile saline in a volume of 500 μL. The dose of 50 mg/kgtypically required 7.5 mg of compound per rat. Several differentprotocols were used to define the efficacy and timing retirements forpotency. Three separate protocols which demonstrate efficacy aredescribed below.

Protocol 1: Compound was administered daily at 50 mg/kg beginning on Day0 and continuing through Day 14, with MBP in CFA administered on Day 0also. As shown in Table II, this treatment substantially reduced theaverage scores for the treated group. The percentage of animalsresponding is also very high with 100% of treated animals-showing eithera total inhibition of symptoms (80%) or reduction of symptoms (20%). N=5for all groups.

                                      TABLE II                                    __________________________________________________________________________           Daily Oral                                                                           Clinical Grade                                                                           Day of                                                                              Effect on                                             Dosing Begun                                                                         at Peak    Peak  EAE Rats                                       Treatment                                                                            at Day 0                                                                             of Disease                                                                           SD  Expression                                                                          (≧ Paresis/Total)                       __________________________________________________________________________    CFA    Phosphate-                                                                           0      0   --    0/5                                                   Buffered                                                                      Saline (PBS)                                                           CFA +  50 mg/kg                                                                             0      0   --    0/5                                            Example 2                                                                     CFA + MBP                                                                            PBS    3.0    0.0 13 & 14                                                                             5/5                                            CFA + MBP +                                                                          50 mg/kg                                                                             1.0    1.22                                                                              12    1/5                                            Example 2                                                                     __________________________________________________________________________

Protocol 2: To determine whether less frequent dosing or dosing at lowerlevels was still effective at suppressing EAE, compound was administeredat either 50 mg/kg or at 10 mg/kg on Day 0 and on alternate days throughDay 14. As shown in Table III, this protocol demonstrated a similareffect on average clinical scores at the peak of disease expression forthe treatment group. The decrease in disease severity was highlysignificant (p≦0.01) for Day 15. Controls run in parallel included CFAonly and MBP in CFA. N=4 for treatment groups. N=8 for controls.

                                      TABLE III                                   __________________________________________________________________________                  Clinical Grade                                                                           Day of                                                                              Effect on                                                    at Peak    Peak  EAE Rats                                       Treatment                                                                            Dosage of Disease                                                                           SD  Expression                                                                          (≧ Paresis/Total)                       __________________________________________________________________________    CFA    PBS    0      0   --    0/4                                            CFA + MBP                                                                            PBS    2.0    0.7 15    5/7                                            CFA + MBP +                                                                          10 mg/kg                                                                             0.6    0.7 14    0/4                                            Example 2                                                                     CFA + MBP +                                                                          50 mg/kg                                                                             0.8    0.6 15    0/4                                            Example 2                                                                     __________________________________________________________________________

Histologically, the Lewis rat EAE model typically shows perivascular andparenchymal inflammation due to an autoimmune myelin-specific T-cellresponse. Examination of histology specimens of the brain slices fromanimals subjected to Protocol 1 demonstrated that leukocyte migrationacross the blood-brain barrier had been completely prevented by the 50mg/kg daily dosing schedule. There was no cuff formation and little CNSinflammation as a result.

The activity of Example 2 as a general inhibitor of inflammation wastested using the Mycobacterium footpad edema assay (MFE) in Wistar rats.Compound was administered daily by gavage at 2 mg/kg, 10 mg/kg, or 50mg/kg.

Male outbred Wistar rats (110-125 g, Charles River Labs, Portage, Mich.)were used in this study. Rats were housed for a minimum of 1 week beforeuse. Food and water were supplied ad libitum. Foot pad edema was inducedfollowing the method described by Martel R. R. and Klicius J.,"Comparisons in rats of the anti-inflammatory and gastric irritanteffects of etodolac with several clinically effective antiinflammatorydrugs", Agents and Actions, 1982;12:295. Briefly, male Wistar rats wereinjected subcutaneously into the right hind footpad with 0.1 mL of 5mg/mL suspension of killed and dried Mycobacterium butyricum (Difco,Detroit, Mich.) in liquid paraffin. Compound was suspended in 0.5%hydroxypropylmethylcellulose (HPMC) containing 0.2% Tween-80 andadministered orally 1 hour before injection. Subsequent doses of thecompound were given 24 and 48 hours after the Mycobacterium. Controlanimals were given vehicle alone. Swelling was assessed on the third dayby subtracting the initial volume (determined immediately following theMycobacterium injection) from the final volume of the treated paw. Pawvolume was determined by mercury plethysmography. The percent inhibitionof edema achieved in each compound-treated group was determined bycomparison with swelling in the vehicle-treated group and the ID₅₀values were determined by regression analysis. Statistical significancebetween experimental groups was evaluated using a Student's t-test. Datais shown in Table IV. All the values for inhibition of the inflammatoryresponse in this model were statistically significant.

                  TABLE IV                                                        ______________________________________                                        Dose (mg/kg) % Inhibition of Swelling                                         ______________________________________                                         2           23                                                               10           27                                                               50           40                                                               ______________________________________                                    

Plasma concentrations of Example 2 peaked at 1 hour post-treatment anddeclined mono-exponentially through the subsequent 4 hours. Cmax andAUC(0-b 4) values increase proportionately with dose. Compound plasmaconcentrations determined from Cmax correspond to 4.62 μM (2-mg/kgdose), 38.8 μM(10-mg/kg dose), and 163 μM (50-mg/kg dose). Thebioavailability of this compound is therefore well in excess of theeffective range of gelatinase A and stromelysin-1 inhibition determinedin the in vitro assays.

A compound of Formula Ia ##STR24## wherein ##STR25## is attached at the1 or 2 position of the A ring and R and R^(a) are each the same ordifferent and each is

hydrogen;

--(CH₂)_(n) -aryl wherein n is as defined above,

--(CH₂)_(n) -heteroaryl wherein n is as defined above,

--(CH₂)_(p) --R₇ --(CH₂)_(q) -aryl wherein R⁷ is O or S and p or q iseach zero or an integer of 1 to 5 and the sum of p+q equals an integerof 5,

--(CH₂)_(p) --R₇ --(CH₂)_(q) -heteroaryl wherein p, q, and R⁷ are asdefined above,

alkyl,

--(CH₂)_(n) -cycloalkyl wherein n is as defined above, or

--(CH₂)_(r) --NH₂ wherein r is an integer of 1 to 9;

a is zero or an integer of 1 to 3;

R⁵ is

OH,

OR⁶ wherein R⁶ is as defined above, ##STR26## wherein R⁶ and R^(6a) areeach the same or different and are as defined above for R⁶, or

NH--OR⁶ wherein R⁶ is as defined above;

R³ and R⁴ are each the same or different and each is

hydrogen,

alkyl,

NO₂,

halogen,

OR⁶ wherein R⁶ is as defined above,

CN,

CO₂ R⁶ wherein R⁶ is as defined above,

SO₃ R⁶ wherein R⁶ is as defined above

CHO, ##STR27## wherein R is as defined above, ##STR28## wherein R⁶ andR^(6a) are each the same or different and are as defined above for R⁶,or ##STR29## wherein R⁶ and R^(6a) are each the same or different andare as defined above for R⁶ ;

W, W¹, Z, and Z¹ are each the same or different and each is CR³ whereinR³ is as defined above, or N providing only one of W or W¹ is N and/oronly one of Z or Z¹ is N; and

Y is ##STR30## wherein R is as defined above, --O--,

--S--(O)_(m) -- wherein m is zero or an integer of 1 or 2,

--CH₂ --, ##STR31## wherein R⁶ is as defined above, ##STR32## wherein R⁶is as defined above, ##STR33## wherein R⁶ and R^(6a) are the same ordifferent and are as defined above for R⁶, ##STR34## wherein R⁶ is asdefined above, ##STR35## wherein R⁶ is as defined above, ##STR36## --CH₂--O--, --O----CH₂ --,

--CH₂ --S(O)_(m) -- wherein m is as defined above,

--S(O)_(m) --CH₂ -- wherein m is as defined above, ##STR37## wherein R⁶is as defined above, ##STR38## wherein R⁶ is as defined above, --CH═N--,or

--N═CH--;

with the proviso that when R⁵ is not NH--OR⁶, at least one of R or R^(a)is not hydrogen; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof may be prepared by reacting acompound of Formula II ##STR39## wherein M is Li or Mg-halogen, and isattached at the 1 or 2 position of the A ring, and R³, R⁴, Y, W, W¹, Z,and Z¹ are as defined above with a compound of Formula III ##STR40##wherein L is halogen,

--OR⁸ wherein R⁸ is methyl or ethyl, or ##STR41## and R, R^(a), a and R⁵are as defined above using conventional methodology such as, forexample, methodology disclosed by Nahm S. and Weinreb S. M., TetrahedronLetters, 1981;22:3815to afford a compound of Formula Ia.

A compound of Formula Ib ##STR42## wherein ##STR43## is attached at the1 or 2 position of the A ring and R⁶ is

hydrogen,

--(CH₂)_(n) -aryl wherein n is zero or an integer of 1 to 5,

alkyl, or

--(CH₂)_(n) -cycloalkyl wherein n is as defined above; and

R³, R⁴, Y, W, W¹, Z, Z¹, R, R^(a), a, and R⁵ are as defined above may beprepared by reacting a compound of Formula Ia with a compound of formula

    H.sub.2 N--OR.sup.6

wherein R⁶ is as defined above using conventional methodology to afforda compound of Formula Ib.

A compound of Formula Ic ##STR44## wherein ##STR45## is attached at the1 or 2 position of the A ring and R⁶ and R^(6a) are each the same ordifferent and each is as defined above for R⁶ and R³, R⁴, Y, W, W¹, Z,Z¹, R, R^(a), a, and R⁵ are as defined above may be prepared by reactinga compound of Formula I_(a) with a compound of formula ##STR46## whereinR⁶ and R^(6a) are each the same or different and each is as definedabove for R⁶ using conventional methodology to afford a compound ofFormula Ic.

Preferred synthetic routes are shown in Schemes 1 to 5 for preparingcompounds of Formula I designated as Formulas Ia to Il.

Thus, in Scheme 1, a compound of Formula IV wherein R³, R⁴, W, W¹, Y, Z,and Z¹ are as defined above is acylated with a compound of Formula IIIawherein L^(a) is halogen, or ##STR47## wherein R⁸ is methyl or ethyl,and R, R^(a), a, and R⁵ are as defined above using conventional.Friedel-Craft (F-C) conditions. For example, a compound of Formula IV isreacted with an acid chloride or anhydride of a compound of Formula IIIaeither neat or in an inert solvent such as, for example,dichloromethane, 1,2-dichloroethane, and the like in the presence of aLewis acid such as FeCl₃, AlCl₃, ZnCl₂, and the like at about -30° C. toabout 150° C. to afford a compound of Formula Ia wherein the moiety##STR48## is attached at the 1 or 2 position of the A ring.

It is understood that the regiochemistry of the products from the F-Cacylation depend upon the electronics of the aromatic ring system andso, only certain regioisomers of Formula Ia will be directly accessibleutilizing this route. For example, F-C acylation will yield thefollowing regioisomers: 2-dibenzofuranyl, 2-dibenzothiophenyl,3-dibenzo-5,5-dioxo-thiophenyl, 2-fluorenyl, and the like when the ringsare unsubstituted.

When the two terminal rings of the linear tricyclic heterocycle aredifferent, the regioselectivity of the F-C will favor the moreelectron-rich ring system. Thus, decreasing the electron density of aring (i.e., by nitration or halogenation) will increase the acylation inthe other ring system. On the other hand, increasing the electrondensity (with substituents such as alkoxy) will tend to favor F-Cacylation in the affected ring.

Compounds of Formula Ib and Formula Ic are prepared from a compound ofFormula Ia using the methodology previously described for converting acompound of Formula Ia to a compound of Formula Ib or a compound ofFormula Ia to a compound of Formula Ic.

Scheme 2 discloses an alternate route to preparing compounds of FormulaI. Thus, a compound of Formula V wherein the aldehyde moiety (CHO) isattached to the 1 or 2 position of the A ring R³, R⁴, W, W¹, Y, Z, andZ¹ are as defined above is reacted with an acrylate of Formula VIwherein R, R^(a), and R⁵ are as defined above using conventionalmethodology to afford a compound of Formula Id wherein the moiety##STR49## is attached at the 1 or 2 position of the A ring and R³, R⁴,W, W¹, Y, Z, Z¹, R, R^(a), and R⁵ are as defined above.

Compounds of Formula Ie and Formula If are prepared from a compound ofFormula Id using the methodology previously described for converting acompound of Formula Ia to a compound of Formula Ib and a compound ofFormula Ia to a compound of Formula Ic.

Schemes 3 and 4 disclose procedures for preparing specific regioisomersof a compound of Formula I. Thus, a compound of Formula VII or FormulaVIIa wherein R³, W, and W¹ are as defined above is reacted withphosphorous oxychloride in dimethylformamide to afford a compound ofFormula VIII or Formula VIIIa, respectively, wherein R³, W, and W¹ areas defined above. A compound of Formula VIII or Formula VIIIa is reactedwith a compound of Formula IX wherein R, R^(a), and R⁵ are as definedabove using methodology previously described for converting a compoundof Formula V into a compound of Formula Id to afford a compound ofFormula Ig or a compound of Formula Ij.

Compounds of Formula Ih, Formula Ii, Formula Ik, and Formula Il areprepared, respectively, from a compound of Formula Ig or Formula Ijusing methodology previously described for converting a compound ofFormula Ia to a compound of Formula Ib or a compound of Formula Ia to acompound of Formula Ic.

Scheme 5 discloses a procedure for preparing optically active sidechains of Formula XVI which can be used to prepare optically activecompounds of Formula I. Thus, R or S 4-benzyl-2-oxazolidinone (FormulaX) is reacted with an acid chloride Formula XI wherein R is as definedabove to afford a compound of Formula XII wherein R is as defined above.

A compound of Formula XII is reacted with a compound of Formula XIIIwherein R^(a) is as defined above in the presence of KHMDS to afford acompound of Formula XIV wherein R and R^(a) are as defined above. Thediastereomers of a compound of Formula XIV are separated followed byreaction with LiOH/H₂ O₂ and subsequent reaction with oxalyl chloride toafford a compound of Formula XV wherein R and R^(a) are as definedabove. A compound of Formula XV is reacted withN,O-dimethylhydroxylamine hydrochloride in the presence of pyridine toafford a compound of Formula XVI wherein R and R^(a) are as definedabove.

Compounds of Formulas II, III, IIIa, IV, V, VI, VII, VIIa, IX, X, XI,and XIII are either known or can be prepared by methods known in theart. ##STR50##

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term "preparation" is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component, with or without other carriers,is surrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing, and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in Unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,lozenge itself, or it can be the appropriate number of any of these inpackaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mgaccording to the particular application and the potency of the activecomponent. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use as agents for the treatment of multiple sclerosis,atherosclerotic plaque rupture, aortic aneurism, heart failure,restenosis, periodontal disease, corneal ulceration, cancer metastasis,tumor angiogenesis, arthritis, or other autoimmune or inflammatorydisorders dependent upon tissue invasion by leukocytes, the compoundsutilized in the pharmaceutical method of this invention are administeredat the initial dosage of about 1 mg to about 100 mg per kilogram daily.A daily dose range of about 25 mg to about 75 mg per kilogram ispreferred. The dosages, however, may be varied depending upon therequirements of the patient, the severity of the condition beingtreated, and the compound being employed. Determination of the properdosage for a particular situation is within the skill of the art.Generally, treatment is initiated with smaller dosages which are lessthan the ,optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstance is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day if desired.

The following nonlimiting examples illustrate the inventors' preferredmethods for preparing the compounds of the invention.

EXAMPLE 1 γ-Oxo-2-dibenzofuranbutanoic acid

A 5-L, three-necked, round-bottom flask is equipped with a mechanicalstirrer, thermocouple thermometer, and a powder funnel with a nitrogeninlet. This flask is charged with 1.5 L of dichloromethane, flushed withnitrogen and aluminum chloride (196 g, 1.44 mol) is added portionwise.The resulting slurry is cooled in a dry ice bath while a dry powderedmixture of dibenzofuran (100 g, 0.595 mol) and succinic anhydride (71.5g, 0.714 mol) is added portionwise. Addition is at a rate sufficient tokeep the reaction temperature less than -30° C. and is completed in 15minutes. The resulting mixture is stirred at this temperature for 2hours then slowly treated with aqueous HCl (375 mL of conc. HCl in 1 Lof solution). During addition of the HCl solution, the temperature iscontrolled to a maximum of 3° C. and addition is completed in 45minutes. The dichloromethane is then removed in vacuo, the aqueousslurry is filtered, and the solid is air dried to give 175 g of whitesolid. This solid is extracted into 4 L of tetrahydrofuran (THF),treated with Darco, and filtered. The filtrate was evaporated leaving acream-colored solid which was recrystallized from 95% ethanol to give180 g of crude product. This solid is recrystallized from toluene (10 Lin 4 portions), and the solids are washed with hexanes then dried invacuo to give 119.5 g (mp 186°-188° C., 75% yield) of the titlecompound.

EXAMPLE 2 4-Dibenzofuran-2-yl-4-hydroximino-butyric acid

A solution of γ-oxo-2-dibenzofuranbutanoic acid (Example 1) (75.5 g) andsodium acetate trihydrate (114.9 g) in methanol (2.5 L) is treated witha solution of hydroxylamine hydrochloride (38.9 g) in water (150 mL ofsolution). The solution is heated to reflux for 3.5 hours thenconcentrated, cooled, and filtered. This solid was washed with waterthen dried in vacuo to give the crude title compound (71.32 g, 89.6% oftheory). This solid was recrystallized from ethyl acetate, washed withhexane, and dried in vacuo to give 53.04 g (68% yield) of the titlecompound; mp 167-168° C. (d).

We claim:
 1. A compound of Formula ##STR51## wherein ##STR52## isattached at the 1 or 2 position of the A ring; wherein X isO, or N--OR⁶wherein R⁶ ishydrogen, --(CH₂)_(n) -aryl wherein n is zero or an integerof 1 to 5, alkyl, or --(CH₂)_(n) -cycloalkyl wherein n is as definedabove; R and R^(a) are each the same or different and each ishydrogen,--(CH₂)_(n) -aryl wherein n is as defined above, --(CH₂)_(n) -heteroarylwherein n is as defined above, --(CH₂)_(p) --R⁷ --(CH₂)_(q) -arylwherein R⁷ is O or S and p or q is each zero or an integer of 1 to 5 andthe sum of p+q equals an integer of 5, --(CH₂)_(p) --R₇ --(CH₂)_(q)-heteroaryl wherein p, q, and R⁷ are as defined above, alkyl,--(CH₂)_(n) -cycloalkyl wherein n is as defined above, or --(CH₂)_(r)--NH₂ wherein r is an integer of 1 to 9; a is zero or an integer of 1 to3; and R⁵ isOH, or NH--OR⁶ wherein R⁶ is as defined above;with theproviso that when X is O, and R⁵ is not NH--OR⁶, at least one of R orR^(a) is not hydrogen; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein one of R or R^(a) is other than hydrogen; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 3. A compound according to claim 1 wherein X is N--OR⁶ ; andcorresponding isomers thereof; or a pharmaceutically acceptable saltthereof.
 4. A compound according to claim 3 wherein R⁵ is OH; andcorresponding isomers thereof, or a pharmaceutically acceptable saltthereof.
 5. A compound according to claim 3 wherein X is N--OH; and R³and R⁴ are each hydrogen; and corresponding isomers thereof; or apharmaceutically acceptable salt thereof.
 6. A compound according toclaim 1 wherein X is O and R⁵ is NH--OR⁶ ; and corresponding isomersthereof; or a pharmaceutically acceptable salt thereof.
 7. A compoundaccording to claim 3 which is selected from the group consistingof:4-Dibenzofuran-2-yl-4-hydroxyimino-butyric acid;2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-4-methyl-pentanoic acid;2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-phenyl-pentanoic acid;4-Dibenzofuran-2-yl-4-hydroxyimino-2-phenethyl-butyric acid;5-(4-Chloro-phenyl)-2-(2-dibenzofuran-2-yl-2-hydroxyimino-ethyl)-pentanoicacid;2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-fluoro-phenyl)-pentanoic,acid;2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-(4-methoxy-phenyl)-pentanoicacid; 2-(2-Dibenzofuran-2-yl-2-hydroxyimino-ethyl)-5-p-tolyl-pentanoicacid; 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-methyl-hexanoic acid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-phenyl-hexanoic acid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-5-phenyl-pentanoic acid;6-(4-Chloro-phenyl)-3-(dibenzofuran-2-yl-hydroxyimino-methyl)-hexanoicacid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-fluoro-phenyl)-hexanoicacid;3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-(4-methoxy-phenyl)-hexanoicacid; and 3-(Dibenzofuran-2-yl-hydroxyimino-methyl)-6-p-tolyl-hexanoicacid.
 8. A compound which is 4-dibenzofuran-2-yl-4-hydroxyimino-butyricacid.
 9. A method of inhibiting a matrix metalloproteinase comprisingadministering to a host suffering therefrom a therapeutically effectiveamount of a compound according to claim 1 in unit dosage form.
 10. Apharmaceutical composition comprising a compound according to claim 1 inadmixture with a pharmaceutically acceptable excipient, diluent, orcarrier.
 11. A pharmaceutical composition adapted for administration asan agent for treating atherosclerotic plaque rupture, aortic aneurism,heart failure, restenosis, periodontal disease, corneal ulceration,cancer metastasis, arthritis, and autoimmune or inflammatory diseasesdependent upon tissue invasion by leukocytes comprising atherapeutically effective amount of a compound according to claim 1 inadmixture with a pharmaceutically acceptable excipient, diluent, orcarrier.
 12. A pharmaceutical composition adapted for administration asan agent for treating multiple sclerosis comprising a therapeuticallyeffective amount of a compound according to claim 1 in admixture with apharmaceutically acceptable excipient, diluent, or carrier.